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Advances in Antibiotic Therapy for Community-acquired Pneumonia

RMpneumonia

Introduction

Community-acquired pneumonia (CAP) is one of the leading causes of death worldwide and is associated with a high economic burden. Although the mortality rate in patients with CAP was dramatically reduced by the introduction of antibiotics in the 1950s, it has not decreased greatly since that time. Recent studies have shown overall mortality rates of 8–15%; however, mortality in patients with CAP who require ICU admission can reach 30%.

This review will focus on the current recommendations for antibiotic treatment, recent findings regarding antibiotic resistance among respiratory pathogens, and advances in antibiotic therapy in the field of CAP.

Newly-developed Antibiotics

Recently, several new antibiotics have been developed with promising results in treating CAP:

Ceftaroline

Ceftaroline is a fifth-generation parenteral cephalosporin that binds to penicillin-binding proteins and prevents the synthesis of bacterial cell wall. It has activity against a broad spectrum of Gram-positive and Gram-negative pathogens, and is the first approved cephalosporin with in-vitro activity against MRSA. The efficacy and safety of intravenous ceftaroline (600 mg twice daily) for the treatment for CAP has been evaluated in several studies. The randomized, double-blind, multicenter, phase III trials – FOCUS 1 and 2 – demonstrated high clinical cure (>82%) and noninferiority of ceftaroline to ceftriaxone among non-ICU hospitalized adults with CAP [Pneumonia Severity Index (PSI) risk classes III–IV]. Clinical cure was defined as total resolution or improvement of all signs and symptoms of pneumonia to the extent that no further antimicrobial therapy was necessary. Finally, these studies found that ceftaroline was well tolerated, with a safety profile similar to that of ceftriaxone and other cephalosporins.

Ceftobiprole

The novel broad-spectrum parenteral cephalosporin ceftobiprole has a microbiological activity against most typical bacterial pathogens causing CAP, including MRSA. The results of a multicenter, double-blind study in which 706 hospitalized adults with severe CAP were randomized to ceftobiprole (500 mg by infusion over 120 min every 8 h) or to ceftriaxone (with or without linezolid) were recently published. Patients who had received antimicrobial therapy for more than 24 h in the previous 3 days and those with suspected or confirmed pneumonia due to atypical agents or aspiration were excluded. No significant differences in baseline characteristics were found between the treatment groups. However, approximately 22% of patients had a PSI score more than 90 in both groups. Regarding end points, ceftobiprole was not inferior to the comparator in terms of clinical cure and microbiological eradication rates.

Ketolides

The ketolides are a subclass of macrolides, which were designed specifically to overcome macrolide-resistant respiratory pathogens. Recently, new ketolides have been developed for treating CAP.

Cethromycin

Two phase III, double-blind, randomized, parallel-group, multicenter studies have been performed to evaluate the efficacy and safety of cethromycin, a novel oral ketolide agent, in patients with mild-to-moderate CAP. In vitro, cethromycin has marked activity against the main causative pathogens of CAP and has the ability to overcome both efflux and methylation mechanisms of macrolide-resistance in S. pneumoniae. Patients were randomly assigned in a 1:1 ratio to receive oral cethromycin (300 mg daily for 7 days) or clarithromycin (250 mg twice daily for 7 days). In comparison with clarithromycin, these two noninferiority studies demonstrated the efficacy and safety of cethromycin in CAP patients. Importantly, the study population only included ambulatory adults with CAP. Clinical cure and bacterial eradication rates did not differ significantly between study groups in the two studies.

Solithromycin

Solithromycin exhibited favorable in-vitro potency and a spectrum of activity against the bacterial pathogens most frequently isolated in CAP and skin structure infections in 10 670 nonduplicated clinical isolates from 52 medical centers in the United States and Europe. In a recent safety data summary of a phase 1 report (171 healthy controls) and a phase 2 report (64 CAP patients), no significant safety concerns were documented.

Quinolones

Quinolones play an important role in the management of CAP. Their use has been increasing over the last decades in patients with CAP.

Nemonoxacin

Nemonoxacin, a novel nonfluorinated quinolone, exhibits potent in-vitro and in-vivo activity against CAP pathogens, including multidrug-resistant S. pneumoniae. In a randomized, double-blind, multicenter study that compared the safety and efficacy of nemonoxacin with levofloxacin in adult patients with mild-to-moderate CAP, a total of 265 patients were included. About 80–85% of cases were PSI risk classes I–II. Oral nemonoxacin (750 mg and 500 mg) administered for 7 days showed clinical and bacteriological success rates as high as those of levofloxacin therapy. No significant difference was noted in drug-related treatment adverse events between the study groups. Among the adverse events, diarrhea, dizziness, and headache were the most frequently reported among nemonoxacin-treated patients.

Zabofloxacin

A phase 2, double-blind, three-arm study performed in the United States to evaluate the safety and efficacy of two dosing regimens of zabofloxacin (a fluoroquinolone antibiotic) compared with levofloxacin in CAP was recently completed and the results are yet to be published. In the preliminary results of a double-blind, randomized, multicenter study in South Korea, zabofloxacin had the same clinical and microbiological cure rates as moxifloxacin in adult patients with mild-to-moderate CAP.

JNJ-Q2

JNJ-Q2 is a novel, fluorinated 4-quinolone that is being developed for the treatment of bacterial pathogens responsible for acute bacterial skin infections as well as respiratory infections, including CAP. In a recent study, JNJ-Q2 showed activity against bacterial causative pathogens of CAP.

KPI-10

Another antibiotic under evaluation and development is KPI-10, a new fluoroquinolone. In isolates collected from medical centers in North America, Europe, Latin America, and Asia-Pacific between 2008 and 2010, KPI-10 demonstrated potent activity against bacteria that are commonly the cause of CAP, including CA-MRSA.

Other Antibiotics

BC-3781 is an investigational semi-synthetic pleuromutilin antibiotic, which recently finished a clinical phase 2 trial in acute bacterial skin and skin structure infections. BC-3781 was very active against respiratory pathogens and its activity was not negatively influenced by resistance to other antimicrobials.

Conclusion

In recent years, a significant increase in the frequency of resistance to the antibiotics that are commonly used to treat CAP has been documented. CA-MRSA and influenza A(H1N1)pdm09 have been identified as causes of severe CAP in the last years. Several new antibiotics, including cephalosporins, ketolides, and quinolones have been developed for treating CAP, with promising results. Most of the current randomized controlled trials have demonstrated the equivalent efficacy of newer antibiotics with regard to conventional antimicrobial therapy, mainly among patients with mild-to-moderate CAP.

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